MODIFICATION OF DISSOLUTION CHARACTERISTICS OF DRUG PARTICLES FOR MULTI-UNIT DOSE APPLICATION.

ABSTRACT

Drugs with short biologic half-life are given frequently in order to maintain the level of the drug in the blood. This is cumbersome and often leads to non-compliance. Hence, the objective of the present study is to develop multiunit dosage forms capable of providing an initial prompt release and a sustained release later to provide prolonged action. This can be achieved by modifying the dissolution profiles of drug particles.Various granulation techniqueswere employed in the preparation of conventional and matrix granules used to prepare two dosage forms (tablets and capsules). The granulation techniques used to form the matrix granules included -melt granulation (i.e. granulation of the drug powder withthe melted wax), granulation with a polymeric gel, a combination of polymeric and melt granulation, and intragranular incorporation of hydrophobic agents (magnesium stearate and talc) in the melt granulations. Conventional granules of test drugs (paracetamol and theophylline) were made by wet massing the drug powder with maize starch mucilage (20%w/v). The granules were subjected to dissolution test. To form the multiunit dosage forms, the conventional and matrix granules were mixed in various proportionsand were either compressed to tablets or filled into capsules. Based on the published pharmacokinetics and dosage regimen of the conventional tablets of theophylline, the multiunit dosage form of the drug was modeled to release the prompt dose (200mg) in the first 1h and the sustained release dose (400mg) in the next 11h at a first order rate constant of 0.24h-1. The resulting multiunit dosage forms were subjected to dissolution test. xviiStability of the multiunit dosage tablets to moisture and heat were determined to obtain their shelf life.Conventional granules gave considerably higher dissolution rates than the rates of the other matrix granules. For instance, the dissolution rates of the conventional granules was 29.3%h-1and for the matrix granules the rates were 11.3%h-1(melt granulation), 12.6%h-1(polymeric granulation), 8.8%h-1(a combination of polymeric and melt granulation) and 9.6%h-1(intragranular incorporation of hydrophobic agents in the melt granulation). Consequently, conventional granules were used as the fast release component and the matrix granules as the sustained release component. Of the various multiunit dosage formulations that were tested only the multiunit dose tablets consisting of the conventional and matrix granules in ratio 1:1 gave the dissolution profile that was consistent with the model. This modified dosage form was stable to moisture and heat and displayed a shelf life of up to 5years. In conclusion, the admixture of the conventional and matrix granules provided a prolonged action dosage form of the test drug with an initial prompt release for immediate relief of clinical symptoms and sustained action.